Use of quinoline-3-carboxamide compounds

ABSTRACT

Method of treating inflammatory bowel disease with a quinoline-3-carboxamide compound comprising ##STR1## structure (I), optionally with substituents for the hydrogen atoms shown: (H 1-9 ), or a pharmaceutically acceptable salt of said compound where: (a) - - - represents that there are two conjugated double bonds between the atoms comprised by the dashed line; (b) X 1  and X 2  are separately selected from an oxygen atom or an NH 9  group, said X 1  and X 2  being bound by a single bond to the ring when attached to H 7  or H 8  and by a double bond when not bound to H 7  or H 8  ; (c) H 1-9  are hydrogens with the provision that H 9  is only present when at least one of X 1  and X 2  is the NH 9  group; (d) H 7  and H 8  are hydrogens that are attached to different atoms selected among X 1 , X 2  and the nitrogen atom (N) in the quinoline ring, for the manufacture of a composition intended for treating inflammatory bowel disease or conditions associated with this disease. Also described are methods for treating inflammatory bowel disease or conditions associated with this disease in which methods the above compounds are administered to a living body. Particularly preferred compounds are N-phenyl-N-methyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide or a salt thereof.

This application is a 371 of PCT/SE95/00244 filed on Mar. 8, 1995.

The present invention concerns the use of quinoline-3-carboxamidecompounds, in particular roquinimex (Linomide®), or a pharmaceuticallyacceptable salt thereof for treating inflammatory bowel disease (IBD)including idiopathic ulcerative colitis (UC) and Crohn's disease.

BACKGROUND OF THE INVENTION

Inflammatory bowel disease (IBD) refers to both idiopathic ulcerativecolitis (UC) and Crohn's disease. These are important chronic medicaldisorders of unknown etiology, characterized by symptoms of inflammationof the bowel with systemic response and also extraintestinalmanifestations.

The cause of IBD is not known. The marked difference in incidence inethnic groups and the tendency of IBD to cluster in families havesuggested genetic or other host factors, but no consistent geneticmarkers have been found. No infectious agent has been consistentlyisolated. Emotional factors are probably not etiologic but they mayexacerbate symptoms. The extraintestinal manifestations, the reportedpresence of antibodies to colonic epithelial cells and of cytotoxicT-cells and the clinical and histological response to immunosuppressiveagents have suggested an immunological basis for the intestinal injury.

The incidence of UC in Scandinavia is 5 to 8 cases/100.000 inhabitants.The incidence of Crohn's disease is increasing but still a bit lowerthan in UC.

UC is confined to colon and rectum only. The cardinal symptoms of acuteUC are diarrhea, rectal bleeding, fever, weight loss and abdominal pain.The disease can be mild but is also associated with complications suchas toxic dilations of the colon and carcinoma of the colon. In Crohn'sdisease, the small intestine and the colon are most often affected, butany part of the gastrointestinal tract may be involved. The onset ofsymptoms are more subtle than in UC. The intestinal manifestations canfor example be abdominal pain, diarrhea, fissures, fistulas, perirectalabscesses. Extra-intestinal manifestations in common for IBD can forexample be nutrional abnormalities, anemia, diseases of the skin(erythema nodosum), arthritis (anchylosing spondylitis) and hepatic andrenal abnormalities.

This formula is a collective formula for the tautomeric structuresII-IV. ##STR2## In formula I-IV: (a) - - - represents that there are twoconjugated double bonds between the atoms comprised by the dashed line(only formula I).

(b) X₁ and X₂ are separately selected from an oxygen atom or an NH⁹group that possibly is substituted, said X₁ and X₂ being bound by asingle bond to the ring when attached to H⁷ or H⁸ and by a double bondwhen not bound to H⁷ or H⁸.

(c) H¹⁻⁹ are hydrogens, with the provision that H⁹ is only present whenat least one of X₁ and X₂ is the NH⁹ group.

(d) H⁷ and H⁸ are hydrogens that are attached to different atomsselected among X₁, X₂ and the nitrogen atom in the quinoline ring saidX₁ and X₂ being bound by a single bond to the ring when attached to H⁷or H⁸ and by a double bond when not bound to H⁷ or H⁸.

The substituents that are to replace H¹⁻⁹ may, according to the priorart, comprise any substituent that gives compounds that can be isolated.

The medical treatment of both UC and Crohn's disease consists mainly ofsulfasalazine and corticosteroids. Mild to moderate acute UC may respondto supportive measures supplemented by sulfasalazine alone.Sulfasalazine is split by bacterial action in the colon to yieldsulfapyridine and 5-aminosalicylate, the latter considered to be activeagent through its local inhibition of prostaglandine and leukotrienesynthesis. If this regimen is insufficient, it can be supplemented bycorticosteroid therapy, given either as oral prednisone or ashydrocortisone administered as a bedtime enema. Acute severe UC may leadto toxic megacolon, a medical emergency requiring systemiccorticosteroids in large doses, coverage by broad spectrum antibiotics,and in some cases emergency colectomy. In Crohn's disease the medicaltreatment is similar to that for UC, with sulfasalazine andcorticosteroids being the main agents used beyond supportive and dietarymeasures. Surgery is most frequently required in the case ofobstruction, fistula formation or abscesses.

Quinoline-3-carboxamide compounds have been suggested aspharmaceuticals. The compounds have comprised the structure given informula I below, optionally with substituents for the hydrogen atomsshown (H¹⁻⁹, where H⁹ is part of X₁ or X₂ as shown in (b) below) and,where appropriate, salts of the compounds: ##STR3## See for instanceIndian Journal of Chemistry Vol 178 (1979) 488-90 (anti-inflammatoryproperties), U.S. Pat. No. 3,960,868 (=GB 1,467,061, analgesic,anticonceptive, anti-inflammatory and anti-allergic properties), U.S.Pat. Nos. 4,547,511 and 4,738,971 (enhancing cell-mediated immunity), WO9015052 (=U.S. Ser. No. 651,234, filed May 31, 1990) (immunomodulator),U.S. Pat. No. 4,107,310 (analgetics) and JP 68023948 (bacteriocides).Patents and patent applications given above are hereby incorporated byreference. In general it can be stated that many of the compoundscomprising structure I are classified as immune modulators withindividual effects spanning the spectra from suppression to stimulationof the immune system. The specific effect achieved depends on thesubstituents.

One of the most important compounds with formula I are the1,2-dihydro-hydroquinoline-3-carboxamides, particularlyN-phenyl-N-methyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide(roquinimex, trade mark Linomide®), i.e. structures I and II with asubstituent for H¹ that equals phenyl, for H² that equals methyl, for H⁸that equals methyl (attached to the nitrogen atom of the quinolinering), with no substituents for H³⁻⁷, with H⁷ attached to X₁, and witheach of X₁ and X₂ equaling an oxygen atom. The compound has double bondsbetween positions 3 and 4 and between position 2 and X₂.

The scientific experimentation with roquinimex has shown that roquinimexhas multiple immunological activities. It has thus been found thatroquinimex increases the proliferative response to T and B cell mitogens28!, enhances antibody production 29! and augments NK cell activity 30,31!. Moreover, its immunostimulating and immunoregulating properties maybe useful in the treatment of tumors 32! and systemic lupuserythematosis 33, 34! as suggested in U.S. Pat. Nos. 4,547,511 and4,738,971.

Published PCT-application WO 91/12804 discloses roquinimex as a drug forthe treatment of retrovirus infections. WO 91/14432 discloses roquinimexas a drug for regenerating lymphoid cells in patients treated withautologous bone marrow transplantation. WO 93/06829 discloses roquinimexas a drug for the treatment of multiple sclerosis. These publishedpatent applications are hereby incorporated by reference.

Quinoline-3-carboxamide compounds according to the present invention arehitherto not known for treating inflammatory bowel disease (IBD).WO92/07833 (POLLAK) discloses dihydroquinoline derivatives which may beused for treating IBD. Anyhow WO92/07833 only teaches compounds with twoquinoline rings, while the compounds according to the presentapplication has one ring. Furthermore the compounds according toWO92/07833 lack the carboxamide structure which is an essentialcharacteristic of the compounds in the present application. WO92/04325discloses naphtalenepropionic acid derivatives which may be used fortreating IBD. Anyhow the quinoline ring according to WO92/04325 is inthe form of a 2-quinolinylmetoxy group which totally lacks thecharacteristic substitution pattern of the compounds according to thepresent invention.

SUMMARY OF THE INVENTION

According to the present invention it has now surprisingly been shownthat treatment with quinoline-3-carboxamide compounds, in particularroquinimex (Linomide®), or a pharmaceutically acceptable salt thereoffor treating inflammatory bowel disease (IBD) including idiopathiculcerative colitis (UC) and Crohn's disease and conditions associatedwith IBD.

Roquinimex may be used as such or as a pharmaceutically acceptable saltthereof. Furthermore, roquinimex can be used in combination with otheragents. Formulations that could be used according to the presentinvention are disclosed in U.S. Pat. No. 4,547,511 col. 11.

Some of the most frequent adverse events seen during treatment withroquinimex are symptoms probably related to an enhanced activation ofthe immune system as they are similar to the symptoms of vitalinfections. The symptoms are muscle and joint pain and stiffness andjoint inflammation. In view of these facts that roquinimex has shown tostimulate the immune response in different experimental and clinicalstudies which also has lead to an adverse event profile of generalmusculoskeletal discomfort, it could not be expected that roquinimexcould show effect on inflammatory bowel disease (IBD).

OBJECTIVES OF THE INVENTION

One major objective of the invention is to provide a method for treatinginflammatory bowel disease (IBD) including idiopathic ulcerative colitis(UC) and Crohn's disease or conditions associated with IBD withquinoline-3-carboxamide compounds, in particular roquinimex (Linomide®),or a pharmaceutically acceptable salt thereof.

Further objectives are to provide drugs to be used for the manufactureof pharmaceutical compositions for the treatment of the conditions givenin the preceding sentence.

Other objectives of the invention will become apparent to one skilled inthe art, and still other objectives will become apparent hereinafter.

EXAMPLE 1

One patient with ulcerative proctitis (ulcerative colitis of the rectum)has so far been subjected to long term treatment with roquinimex. Thepatient received his diagnosis ulcerative proctitis in 1965. In 1983 hegot renal cancer. In spite of treatment with medroxiprogesteron andinterferon alpha his renal cancer progressed. In May 1988 he startedtreatment with roquinimex in a phase I-study. Roquinimex was given in anoral solution once a week with escaling doses, 0.05-0.6 mg/kg. Hisulcerative proctitis was at that time treated with sulfasalazine(Salazopyrin®). During roquinimex treatment his ulcerative proctitisimproved and the dose of sulfasalazine was decreased after about fiveweeks. End of July 1988 he resumed treatment with roquinimex with a doseof 15 mg twice weekly in a phase II study in patients with renal cellcarcinoma. About two months later there were no clinical signs orsymptoms of his ulcerative proctitis and treatment with sulfasalazinewas withdrawn.

He received later a complete response of his renal cancer. Theroquinimex treatment was terminated in March 1992 and he is at this datestill in complete remission both with respect to the ulcerativeproctitis and his renal cancer.

We claim:
 1. A method for treating a patient suffering from, or at riskfor acquiring, inflammatory bowel disease, comprising administering tothe patient an effective therapeutic dose ofN-phenyl-N-methyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamideor tautomers thereof, or a pharmaceutically acceptable salt thereof. 2.The method of claim 1, wherein the compound is administered orally. 3.The method of claim 1, whereby said compound is administered byinjection.
 4. The method of claim 1, whereby said compound isadministered parenterally.
 5. The method of claim 1, 2, 3, or 4, whereinthe effective amount is from about 0.01 to about 10 mg/kg body weightand the amount is administered from once daily to once every two weeks.6. The method of claim 5, wherein the effective amount is from about0.05 to about 1 mg/kg body weight.